Shock Induced Alterations in the Inflammatory Response: W.J. Mileski, M.D., UTSMC, Dallas, TX Multiple Organ Failure Syndrome (MOFS) is an important cause of death in the intensive care unit resulting in more than 70,000 deaths per year in the United States. Generalized activation of the inflammatory response appears to play a central role in the pathogenesis of MOFS. Successful host response to injury or infection requires balanced activation of advantageous local inflammatory events coordinated with systemic counter-regulatory controls to prevent generalized dissemination of the inflammatory response. Tumor necrosis factor (TNFalpha), interleukin-1 (IL-1beta), and neutrophils (PMN's) have been identified as central mediators or effectors in the inflammatory response. Counter-regulatory mechanisms of the inflammatory cascade are less clearly defined. The neuropeptide alpha-melanocyte stimulating hormone (alphaMSH), interleukin 4 (IL-4), and interleukin 10 (IL-10), have been reported to have inhibiting effects on monocytes and the inflammatory response. General hypothesis: An insult of tissue trauma or shock may alter the balance between the pro-inflammatory mediators and opposing counter- regulatory mechanisms, thus allowing the escape of the local inflammatory response to the systemic level. Such a disequilibrium could occur as a result of increased (primed) proinflammatory mechanisms (i.e., TNFalpha, IL-1beta, PMNs), or by reducing or depleting the counter-regulatory mechanisms (alphaMSH, IL-4, and IL-10) or some combination of inflammatory priming and diminution of counter-regulatory mechanisms. Sub-hypotheses: (1) LPS-induced activation of inflammatory mediators (TNFalpha, IL-1beta, and/or PMNs) is potentiated following hemorrhagic shock, (2) LPS induced activation of counter-regulatory mediators of inflammation (alphaMSH, IL-4, and/or IL-10) is reduced after hemorrhage, or is not commensurate with the potentiated pro-inflammatory components. To test these hypotheses New Zealand white rabbits will be used in a model of sequential injury; hemorrhagic shock and resuscitation followed by administration of bacterial endotoxin (LPS) at intervals from 24-96 hours post shock. TNFalpha, IL-1beta, IL-6, alphaMSH, IL-4, and IL-10 levels following LPS administration in sham-hemorrhaged and previously hemorrhaged animals will be measured in plasma, along with in vitro production of these mediators by alveolar macrophages and peripheral blood lymphocytes isolated from the experimental animals. To assess changes in PMN activation, PMN accumulation in lung, liver, kidney and intestine following LPS administration in sham-hemorrhaged and previously hemorrhaged animals will be quantitated by morphometric and biochemical (MPO) analysis. Changes in the adherence and aggregation of PMNs isolated from normal and hemorrhaged animals in response to stimulation with LPS or TNFalpha will be measured in vitro. This serial monitoring of changes n the proinflammatory and counter-regulatory components of the inflammatory cascade in a model of systemic inflammatory injury will allow tests of the hypotheses presented.